The Precursors of Stroke Incidence and Prognosis study has contributed to our understanding of the epidemiology of stroke in the Framingham Original cohort since 1981. In recent years the Framingham Offspring cohort has been added. We propose expanding the study to include genetic epidemiological and molecular genetic studies of stroke and stroke risk factors. We will continue to document and follow all new stroke cases in Framingham. In addition, we will focus on the Offspring and Omni (minority) Cohorts by obtaining: Brain Magnetic Resonance Imaging (MRI) for silent cerebral infarcts and white matter hyperintensities, and (2) a neuropsychological test battery. About 15 percent will have "silent strokes" of greater than or equal to 3 mm in size on MRI and 85 percent may be expected to have some degree of WMHI's. The proposed phenotype for the genetic studies of stroke in Framingham is: clinical strokes; SCI's; quantitative SCI volume and WMHI volume on MRI. The risk factors associated with this stroke phenotype have already been collected in Framingham including: confirmed parental and sibling stroke; hypertension and higher blood pressure levels; lower forced expiratory volume in 1 second; cigarette smoking; diabetes; and, prior cardiovascular disease, stroke or transient ischemic attack. Of particular interest are the availability measures of hemostasis and platelet aggregability: platelet glycoprotein receptor GPIIb/IIIa polymorphism; hemostatic factors including plasma fibrinogen levels, plasminogen activator inhibitor type 1 (PAI-1) tissue plasminogen activator (tPA), factor V and VII, von Willebrand, platelet aggregability, and blood viscosity measures. Finally, a 10 cM genome scan of all 355 large extended families in Framingham has been performed. We propose linkage analyses and molecular genetic studies to identify the genetic loci responsible for fibrinogen and PAI-1 levels and for the stroke and MRI phenotypes. Until now only educated guesses among possible candidate genes for stroke risk were possible, these studies prioritize the recognized candidates and to identify new loci.